The Instrumented Fetal Sheep as a Model of Cerebral White Matter Injury in the Premature Infant

Abstract

Despite advances in neonatal intensive care, survivors of premature birth remain highly susceptible to unique patterns of developmental brain injury that manifest as cerebral palsy and cognitive-learning disabilities. The developing brain is particularly susceptible to cerebral white matter injury related to hypoxia-ischemia. Cerebral white matter development in fetal sheep shares many anatomical and physiological similarities with humans. Thus, the fetal sheep has provided unique experimental access to the complex pathophysiological processes that contribute to injury to the human brain during successive periods in development. Recent refinements have resulted in models that replicate major features of acute and chronic human cerebral injury and have provided access to complex clinically relevant studies of cerebral blood flow and neuroimaging that are not feasible in smaller laboratory animals. Here, we focus on emerging insights and methodologies from studies in fetal sheep that have begun to define cellular and vascular factors that contribute to white matter injury. Recent advances include spatially defined measurements of cerebral blood flow in utero, the definition of cellular maturational factors that define the topography of injury and the application of high-field magnetic resonance imaging to define novel neuroimaging signatures for specific types of chronic white matter injury. Despite the higher costs and technical challenges of instrumented preterm fetal sheep models, they provide powerful access to clinically relevant studies that provide a more integrated analysis of the spectrum of insults that appear to contribute to cerebral injury in human preterm infants.

Astrocytes and microglia in acute cerebral injury underlying cerebral palsy associated with preterm birth

“…In preclinical studies, the response to injury is highly dependent on brain maturity. The susceptibility of the periventricular white matter does not appear to be related to greater ischemia in that region, at least in the sheep (11). Rather, it is closely correlated with the relative vulnerability of late oligodendrocyte progenitors in rabbit, sheep, and human (11,12).…”

“…The susceptibility of the periventricular white matter does not appear to be related to greater ischemia in that region, at least in the sheep (11). Rather, it is closely correlated with the relative vulnerability of late oligodendrocyte progenitors in rabbit, sheep, and human (11,12). Furthermore, in vitro, central premyelinating axons are reported to be much more vulnerable to ischemic injury than adjacent myelinated axons or smaller axons that had not reached the stage of radial expansion (13), likely contributing to the high risk of axonopathy in necrotic periventricular white matter lesions (14).…”

Programming the brain: Common outcomes and gaps in knowledge from animal studies of IUGR

“…The patterns of restriction in 154 these models also differ from that in human IUGR due to placental insufficiency, which 155 progressively worsens during pregnancy [ Figure 2,14]. Differing types of nutrient restriction have 156 been utilised, particularly in rats, with some restricting dietary protein, while others impose global nutrient restriction accounts in part for variable reductions in birth weight (Table 2).…”

Global Hypoxia-Ischemia Induced Inflammation and Structural Changes in the Preterm Ovine Gut Which Were Not Ameliorated by Mesenchymal Stem Cell Treatment

“…The fetal sheep was used as a validated animal model to study the effects of fetal HI on organ development (33). In addition, fetal instrumentation in utero enabled us to test potential therapeutics to prevent organ damage after global HI (34)(35)(36).…”